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a Relative RNA expression of HOXB-AS3 in seven AML cell lines. HOXB-AS3 lncRNA expression in healthy hematopoietic cells and leukemic blasts. Finally, we demonstrate the potential value of HOXB-AS3 as a therapeutic target in preclinical AML xenograft models. We perform assays to identify the protein interactors of HOXB-AS3 and describe its functional role in regulating rRNA transcription and ribosomal biogenesis in leukemic blasts. Herein, we dissect the functional role of HOXB-AS3 in NPM1mut AML. HOX gene loci also contain lncRNAs that are involved in cell differentiation and cancer pathogenesis (e.g., HOTAIR, HOTTIP, HOTAIRM1), mainly by regulating the expression levels of protein-coding HOX genes 29, 30, 31.Ĭonsidering the aberrant expression of the HOX genes in AML with mutated NPM1 ( NPM1mut) and the role of lncRNAs in regulating HOX gene expression, we hypothesized that HOXB-AS3 overexpression could have biologic significance in NPM1mut AML. HOX genes are important regulators of embryonic and hematopoietic cell development, which have been implicated in leukemogenesis 28. A lncRNA embedded in the HOXB locus and named HOXB-AS3 was identified among the most highly upregulated lncRNAs in CN-AML patients with NPM1 mutations. In addition, recurrent prognostic gene mutations in AML, including NPM1 mutations, have been reported to associate with distinctive lncRNA signatures 24, 25, 27. In AML, prognostic lncRNA transcripts whose expression independently associates with the outcome of AML patients have recently been identified 24, 25, 26. Deregulated expression of lncRNAs is an important molecular event in many types of cancer 18, 19, 20, 21, 22, 23. Long non-coding RNAs (lncRNAs) constitute a distinct subset of non-protein-coding RNA molecules that are longer than 200 nucleotides and regulate many key cellular functions 17. These findings support the critical role of NPM1 mutations in leukemogenesis. Mechanistically, expression of a humanized mutant Npm1 allele in a conditional knock-in mouse model causes HOX gene overexpression and late-onset myeloid leukemia 16. At the molecular level, NPM1-mutated CN-AML is associated with a distinctive mRNA-expression profile characterized by HOX gene family overexpression and CD34 negativity 6, 15. NPM1 mutations in AML result in the introduction of a nuclear export signal at the C-terminus of the NPM1 protein, which leads to the aberrant localization of the mutant protein in the cytoplasm 4, 13, 14. The wild-type NPM1 gene encodes an ubiquitously expressed protein that shows strong nucleolar localization 7, shuttles between the nucleus and cytoplasm 8 and regulates important cellular functions such as transcription 9 and maturation 10, 11 of ribosomal RNA (rRNA) and nuclear export of ribosomal proteins 12. NPM1 mutations are detected in ~60% of patients with cytogenetically normal AML (CN-AML) and associate with a favorable clinical outcome 4, 5, 6. Mutations in the NPM1 gene are among the most frequent and clinically relevant genetic alterations in AML, and define a distinct subtype of AML in the World Health Organization classification of acute leukemias 3. Recurrent chromosome aberrations and gene mutations have been implicated in leukemogenesis and are used in the clinic to risk-stratify treatment of AML patients 2. Nature Communications volume 10, Article number: 5351 ( 2019)Īcute myeloid leukemia (AML) is a highly heterogeneous disease with regard to its underlying genetic abnormalities and clinical course 1. The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia